New synthetic methods for the preparation of macrocyclic amido-N donor ligands are provided. The primary method of the present invention involves in general only two synthetic steps. In the first step, an α or β amino carboxylic acid is allowed to react with an optimal (approximately stoichiometric)...http://www.google.es/patents/US6051704?utm_source=gb-gplus-sharePatente US6051704 - Synthesis of macrocyclic tetraamido-N ligands

New synthetic methods for the preparation of macrocyclic amido-N donor ligands are provided. The primary method of the present invention involves in general only two synthetic steps. In the first step, an α or β amino carboxylic acid is allowed to react with an optimal (approximately stoichiometric) amount of an activated malonate or oxalate derivative with mild heating. Upon completion of the double coupling reaction, hydrolysis of the reaction mixture yields a diamide containing intermediate (a macro linker). In the second step, stoichiometric amounts of a diamine, preferably an orthophenylene diamine, are added to the macro linker intermediate in the presence of a coupling agent and heat. This second double coupling reaction, is allowed to proceed for a period of time sufficient to produce a macrocyclic tetraamido compound. The substituent groups on the α or β amino carboxylic acid, the malonate, and the aryl diamine may all be selectively varied so that the resulting tetraamido macrocycle can be tailored to specific desired end uses. The macrocyclic tetraamide ligand may then be complexed with a metal, such as a transition metal, and preferably the middle and later transition metals, to form a robust chelate complex suitable for catalyzing oxidation reactions.

Imágenes(3)

Reclamaciones(19)

What we claim is:

1. A method for producing a macrocyclic tetraamido compound comprising:

(1) reacting an amino carboxylic acid with an activated derivative selected from the group consisting of oxalates and malonates in the presence of a supporting solvent and heat to form an intermediate; and,

(2) adding thereto a diamine in the presence of solvent and a coupling agent, and heating the resulting mixture for a period of time sufficient to produce macrocyclic tetraamido compounds.

2. The method of claim 1 wherein the amino carboxylic acids are selected from the group consisting of α and β amino carboxylic acids and combinations thereof.

6. The method of claim 1 wherein the supporting solvent is an aprotic solvent.

7. The method of claim 1 wherein the coupling agent is selected from the group consisting of a phosphorous halide compound and pivaloyl chloride.

8. The method of claim 1 wherein the diaminie is added under anhydrous conditions.

9. The method of claim 1 wherein the heat to form the intermediates (1) is at a temperature equal to or less than about 70° C.

10. The method of claim 1 wherein the amino carboxylic acid is an α spiro-cyclohexyl amino carboxylic acid and the supporting solvent is added in multiple aliquots at periodic intervals to yield a bis-cyclohexyl intermediate and an oxazalone species.

11. The method of claim 10 further comprising the step of hydrolyzing the oxazalone species in the presence of solvent to the bis-cyclohexyl intermediate.

12. The method of claim 11 further comprising extracting the bis-cyclohexyl macrocyclic tetraamido compound into an organic solvent, washing and further separating residual oxazalone species with pentane extraction.

13. The method of claim 1 further comprising complexing a transition metal to the amides of the macrocyclic tetraamido compound.

deprotonating the amides of the macrocyclic tetraamido compound with a base;

adding a metal ion; and,

oxidizing to produce a metal chelate complex having the structure: ##STR41## wherein M is the metal; L1 is any labile ligand; Z is N; Ch1, Ch2, Ch3 and Ch4 are oxidation resistant components which are the same or different and which form five- to six-membered rings with the adjacent ZMZ atoms.

15. The method recited in claim 14 wherein the oxidation step comprises exposure to one of air, oxygen, chlorine, bromine or benzoyl peroxide.

16. The method recited in claim 14 wherein the base is a noncoordinating organic soluble base.

17. The method of claim 14 wherein the base is selected from the group consisting of lithium bis-trimethylsilylamide, lithium di-isopropyl amide, t-butyl lithium, n-butyl lithium, and phenyl lithium.

18. The method of claim 14 further comprising combining the metal chelate complex with an oxygen atom transfer oxidant.

19. The method of claim 1 further comprising:

(3) attaching a protecting group to the diamine prior to adding the diamine to the intermediate;

(4) adding the protected diamine to the intermediate and refluxing;

(5) adding to the product thereof, THf, a base and a metal salt in the presence of oxygen to form the metallated amino pendant macrocyclic tetraamido compound in a protected form; and

(6) removing the protecting group.

Descripción

This invention was made in part with funding from the National Institute of Health, Contract No. GM-44867 and the National Science Foundation, Contract No. CHE9319505. The U.S. government may have rights in this invention.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to synthetic methods for producing macrocyclic compounds, and more particularly, to synthetic methods for producing tetraamido macrocyclic ligands and metal chelate complexes as pre catalysts for oxidation reactions.

2. Description of the Invention Background

Complexes of high oxidation state transition metals are known to function as oxidants in numerous biological reactions under the influence of a protein matrix and in recent years a widespread interest in understanding the mechanism of action and the reactivity of certain monooxygenase catalysts has developed. However, in the absence of a protein matrix to direct the oxidizing power towards a specific substrate, high oxidation state transition metal complexes tend to exhibit low oxidative selectivity and will instead oxidize any available substrate. Since the ligand complement is available in high local concentration as a possible substrate, oxidative degradation of the ligand complement has been a formidable impediment to obtaining long lived oxidation catalysts in the absence of a stabilizing matrix.

An azide based synthetic route to macrocyclic tetraamido ligands is described in Uffelman, E. S., Ph.D. Thesis, California Institute of Technology, (1992). Synthesis of the tetraamido ligands via the azide based route developed by Uffelman proceeds generally as follows: ##STR1##

Synthesis of an aryl bridged tetraamido ligand via the azide based route proceeds as follows: ##STR2##

The yield of the azide based method is about 25% for the final ring closing step but only about 5-10% for the combined sequence of steps starting from the diamine. This method generates new C--N bonds via formation of azide intermediates. The generation of the C--N bonds, however, is not very effective, at least as to yield. With each step of the process, the yield is reduced further so that the overall yield of the desired tetraamido ligand is comparatively low. Furthermore, the azide based method produces high energy intermediates.

There is a need for an alternative method of producing tetraamido ligands. There is also a need to improve the yield of such ligands. Finally, there is a need for a method of producing tetraamido ligands that are resistant to oxidative degradation and in which the various substituent groups can be controlled to tailor the ligands and the metallo complexes they form for specific end uses.

SUMMARY OF THE INVENTION

The foregoing needs are met by the method of the present invention and the compounds produced thereby. This method provides powerful new synthetic routes for the preparation of macrocyclic amido-N donor ligands, and particularly those with oxidatively robust substituents. The primary method of the present invention substantially increases the yield, and reduces the number of steps, as well as the time and the cost of the process as compared to the prior art azide method. Importantly, the new synthetic method reduces the hazards inherent to the azide method due to that method's high energy intermediates.

The method of the present invention includes in general two steps. In the first step, an amino carboxylic acid, preferably an α or β amino carboxylic acid, is dissolved in a supporting solvent and heated with an activated derivative selected from the group consisting of oxalates and malonates, such as a substituted malonyl dichloride in the presence of a base, to form an intermediate. The amino carboxylic acid is preferably in an amount that is approximately the stoichiometric amount, and most preferably in an amount somewhat greater than the stoichiometric amount. Any solvent suitable for performing acylations will suffice. However, if the solubility of the amino acid starting materials in organic solvents is limited, the preferred solvents are pyridine, dimethyl formamide (DMF) or any suitable aprotic solvent. Following completion of the selective double coupling reaction, typically 72-114 hrs when pyridine is used as the solvent/base, a diamide dicarboxyl-containing intermediate, sometimes referred to herein as a macro linker, is isolated. If acyl chlorides are employed in the synthesis of such macro linker intermediate, both the yields and ease of isolation of the intermediate can be improved by ensuring that the heat added in step 1 does not exceed 70° C. and that any reactive intermediates formed during the acylation reaction are carefully hydrolyzed prior to workup.

In the second step of the method of the present invention, a diamine is added to the intermediate in the presence of a solvent and a coupling agent. The resulting mixture is heated and the reaction is allowed to proceed for a period of time sufficient to produce macrocyclic tetraamido compounds via a selective double coupling reaction, typically 48-72 hours at reflux when pyridine is employed as the solvent. Longer ring closure times are necessary if substantial steric hindrance or hydrogen bonding substituents are present. Typically, stoichiometric amounts of an aryl or alkyl diamine, for example, an orthophenylene diamine, are used.

The preferred coupling agents are phosphorus halide compounds, such as PBr3, PCl3 or POCl3, or pivaloyl chloride. The phosphorus halides are employed as powerful dehydrating agents for the condensation of amines and carboxylic acids to form amides. Pivaloyl chloride on the other hand is preferred for the preparation of mixed anhydride and oxazalone intermediates. Yields are improved if moisture is excluded during the second, ring closing step.

The substituent groups on the α or β amino carboxylic acid, the activated oxalate or malonate derivative, and the diamine may all be selectively varied so that the resulting tetraamido macrocycle can be tailored to specific desired end uses. This highly efficient streamlined synthesis not only tolerates a comparatively wide range of functional groups, but also employs relatively low cost reagents and is compatible with large scale operation, all of which are highly desirable synthetic features.

Variation of the substituents has little or no effect on the methodology. In varying the macrocycle, however, it is important to preserve the amide framework. The macrocycle will be made up of 5- and 6-membered rings, in a 5,5,5,5 pattern, a 5,5,5,6, pattern, a 5,6,5,6 pattern, a 5,5,6,6, pattern, a 5,6,6,6 pattern, or a 6,6,6,6 ring pattern which will be described in more detail below.

A modified version of the method of the present invention adds protection/deprotection steps in order to generate the intermediate species. Functional groups of some starting materials may require protection during the acylation reaction of step one or the subsequent macrocyclization reaction to preserve some particular functionality. A deprotection step is then carried out before and/or after the macrocyclization step (step two of the primary method of the invention) to yield the final deprotected product. Techniques for protection and deprotection of a variety of functional groups are known to those skilled in the art. The particular techniques depend on the functional group and starting material of interest. The intermediate species (possibly in a protected form) are then coupled via a double coupling reaction analogous to that described above in order to generate the desired tetraamido macrocycle. Although the modified version of the method is in general longer and more complex, it provides a much wider range of macrocyclic tetraamide compounds due to the much greater degree of synthetic versatility that is conveyed by the use of protecting/activating groups.

Once the macrocyclic tetraamido ligand has been prepared, the macrocyclic compound may be complexed with a wide range of metal ions, preferably a transition metal, and most preferably a group VIA, VIIA, VIII or IB transition metal, to form a chelate complex of the formula wherein ##STR3## M is the metal, Z is N, L1 is any labile ligand, Ch1, Ch2, Ch3 and Ch4 are oxidation resistant components of the chelate system which are the same or different and which, as stated above, form five- or six-membered rings with the adjacent ZMZ atoms.

Complexation is achieved by the following method. The macrocyclic ligand is dissolved in a supporting solvent, usually THF, and deprotonated by treatment with a base, preferably lithium bis-trimethylsilylamide, lithium di-isopropyl amide, t-butyl lithium, n-butyl lithium, or phenyl lithium. Any base that removes the amide N--H protons will suffice, but noncoordinating organic soluble bases are preferred. After the ligand is deprotonated, a metal ion is added. The resulting intermediate, a comparatively low valent ligand metal species, is then oxidized., The oxidation step is preferably performed with air, chlorine, bromine, or benzoyl peroxide to produce the metal chelate complex usually as a lithium salt. Metathesis of the resulting complex to form a tetraalkyl ammonium, tetraphenyl phosphonium or bis(triphenylphosphoranylidene) ammonium (PPN) salt tends to yield metal chelate complexes that are easier to purify as compared to the lithium ion containing complexes. The purified metal chelate complex, can then be used to catalyze oxidation reactions.

If the complex is then combined with a strong O-atom transfer oxidant, preferably a peroxide, such as hydrogen peroxide, t-butyl hydroperoxide, or cumyl hydroperoxide, a ligand-metal IV, V or VI oxo intermediate is produced. For cases in which oxidatively robust substituents have been employed to generate the ligand framework robust high oxidation state oxo containing species can be prepared, and it is believed that these high valent oxo containing species are the active transfer agents in catalyzing a number of oxidation reactions.

When a low valent metal species is exposed to a peroxide or other [O] containing oxidant the metal attracts and binds the oxygen from the oxidant. Depending on the metal, the bond between the metal and the oxygen will be very strong or may be only strong enough to remove the oxygen from the oxidant for subsequent transfer to another constituent.

If the metal is a metal III ion, the resulting oxo species will in general be a metal V ion. If the metal is a metal IV ion, the resulting oxo species will in general contain a metal VI ion. The combined stabilizing effect of the macrocyclic ligand and the participation of the d electron count at the metal center in controlling the degree of bonding to an oxo ligand tends to favor early transition metal complexes forming very strong oxygen-metal bonds to yield stable oxides. The middle and later transition metals tend to remove the oxygen from the oxidant, bind to the oxygen for a period of time and then transfer the oxygen to a substrate. In the metal ligand system produced by the method of the present invention, the middle and later transition metals, therefore, tend to promote the transfer of oxygen. In addition, to its stabilizing effect, the ligand also exerts influence on the metal properties. By controlling the metal, the electron density of the macrocycle, the charge on the complex, and the bond strength/bond order to the coordinated oxo ligand, the metal ligand complex can be fine tuned to achieve a complete range of oxygen transfer abilities, from stable oxides to high valent oxidation catalysts.

In the preferred embodiment, the axial ligand, L1, is labile because it occupies its position relative to the metal until the chelate system is introduced into a solution containing an oxidant. The labile ligand will dissociate and will be replaced by the oxidant, most generally an O-atom transfer agent, but also any general oxidant that can serve to activate the metal ion to perform catalysis. Preferred labile ligands.include, but are not limited to, the chloride anion, halide ions in general, CN-, H2 O-, OH-, ROH, NH3, or any amine, carboxylate, phenol or phenoxide, pyridine, ether, sulfoxide, ketone, or carbonate. The oxidation site in the metal complexes of aromatic-ring containing macrocycles can be manipulated by the choice of axial ligands as well as by the ring substituents.

As stated, the substituents on the components within the chelate system do not participate in the synthesis reaction so numerous variations are possible. If, for example, the ligand is to provide an oxidatively robust compound and catalyst, there are certain restrictions placed on the substituent. It is believed that hydrogen atom abstraction occurs between the malonate linker's substituents and the axial ligand bound to the central metal atom of the ultimate chelate system. The abstraction is believed to lead to oxidative degradation. The components of the chelate system are preferably selected from those having substituents that are resistant to oxidative degradation by virtue of having good bond strengths and/or of being comprised of species that have low conformational freedom to prevent attainment of conformers which are conducive to intramolecular oxidative degradation. Compounds which satisfy this criteria are described in co-pending U.S. patent application of T. J. Collins et al., for "Long-Lived Oxidation Catalyst Compounds", filed on even date herewith, the disclosure of which is hereby incorporated herein by reference. If oxidative degradation is not a concern, the components of the chelate system may be chosen from those having a much broader range of possible substituents.

The degree of resistance to oxidative degradation depends in part on the intended use of the resulting chelate system and catalyst. For example, if the reaction which the catalyst is intended to affect occurs early on in a process, a long lived catalyst may not be as critical. In that event, the substituent groups of the malonate starting material can have weaker bonds or exhibit conformational freedom. Examples include ethyl groups and longer chain alkyls. The activated oxalate or malonate derivative is believed to contribute to the most sensitive part of the resulting macrocylic ligand. The malonate may be unsubstituted, monosubstituted or disubstituted. Preferred substituent groups on the malonate include methyl, ethyl, halogen, hydrogen, CF3 and a spiro-cyclopentyl or spiro-cyclohexyl ring in place of the disubstituted positions, R1 and R2.

DESCRIPTION OF THE FIGURES

FIG. 1 is an example of substitution at the variable positions within the Bridge-Arm-Linker-Arm macrocyclic tetraamides described herein;

FIG. 2 is an illustration of a long necked RB flask used for controlling the atmosphere of the macrocyclization reactions of the present invention at reflux temperatures greater than 100° C.;

FIG. 3 is a schematic view of an amino pendant macrocyclic metal complex covalently bound to an acrylic polymer;

FIG. 4 is a schematic view of a recyclable metallo-oxidant system; and

FIG. 5 is an illustration of several chelate complexes formed from the macrocyclic ligands synthesized by the method of the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The primary method of the present invention provides a more efficient, less costly, higher yield synthesis of macrocyclic tetraamido ligands than has been heretofore available. Further, the primary method of the present invention permits the synthesis of a wide range of variants, many of which are difficult to synthesize via the prior art azide based synthetic method.

The primary method proceeds generally as shown in sequence 1. Sequence 2 shows a modified version of the primary method that employs protecting groups. Specific examples of the application of the primary method to the synthesis of some particular macrocyclic tetraamides are shown in sequence 3. For convenience of classification herein, the starting materials that are composed of diamine functionalities are sometimes referred to as "Bridges" (B), the starting materials composed of diacid functionalities are sometimes referred to as "Linkers" (L), and the starting materials composed of amine/acid functionalities are sometimes referred to as "Arms" (A). The arms of the macrocyclic compound are generally more resistant to degradative attacks than the linker. ##STR4## Sequence 1 is a generalized synthesis of macrocyclic tetraamides having a (B--A--L--A--) configuration, from α-amino carboxylic acids via the primary method of the invention. A diamide dicarboxyl-containing intermediate, sometimes referred to herein by the short hand designation, "macro linker intermediate" or simply the "intermediate" (A--L--A) is preformed without the use of protecting groups via a selective double coupling reaction wherein an α amino carboxylic acid, the arms, A, and an activated malonic acid derivative, the linker, L, in solvent are heated to form the macro linker intermediate. The macro linker intermediate is then coupled to a diamine, the bridge, B, in another selective double coupling reaction that employs a solvent, a coupling agent and heat. The synthetic methodology is highly streamlined and tolerates a wide range of functional groups. A wide range of macrocyclic tetraamides bearing different electronic or steric substituents have been prepared in this manner in good yield. ##STR5## Sequence 2 is a generalized synthesis of macrocyclic tetraamides having a (B--A--L--A--) configuration, from β-amino carboxylic acids via a modified version of the primary method of the invention. The same basic approach employed with α-amino carboxylic acid starting materials is applied to β-amino carboxylic acid starting materials. For some amino carboxylic acids use of a protecting group may be desirable, as shown in sequence 2. A macro linker intermediate (A--L--A) is preformed via a selective double coupling reaction wherein a protected β-amino carboxylic ester arm, A, and an activated malonic acid derivative linker, L, in solvent are heated to form the intermediate, which after deprotection can then be coupled to the diamine bridge, B, in another selective double coupling reaction to yield a wide variety of substituted macrocyclic tetraamides with an expanded ring size compared to those that have been prepared from α-amino carboxylic acids.

The macro linker intermediate (A--L--A) can be made on a large scale in batch or continuous processing via direct reaction of a substituted malonyl dihalide with a solution (preferably a pyridine solution) of an α or β-amino carboxylic acid or ester. Many examples of the reaction proceed in good yield without the use of protecting groups at temperatures preferably less than or equal to about 70° C. Some examples may require the use of protecting groups and these reactions generally proceed in excellent yield. The intermediate can be separated into batches and each separate batch further reacted with a wide range of diamine bridging compounds having different steric or electronic substituents in the presence of a coupling agent. For the α-amino carboxylic acid case, the ring closing step proceeds for 48-120 hours and is ideally substantially moisture free, as in sequence 3. A wide range of rtetraamido macrocycles having finely tuned electronic properties can be synthesized at a considerable cost savings over the prior art azide method. ##STR6##

Sequence 3 is a specific example of the preparation of macrocyclic tetraamides having a (B--A--L--A--) configuration from α-amino carboxylic acid starting materials. An α-amino carboxylic acid is mixed with an activated malonate in pyridine at temperatures less than 70° C. After the selective double coupling reaction is complete, 72-144 hrs, the macro linker intermediate (A--L--A) is isolated. In a second step a diamine, preferably an o-phenylene diamine, is added to a pyridine solution of the macro linker intermediate in the presence of a coupling agent, preferably PCl3 or pivaloyl chloride. The ring closure, a double coupling reaction, is allowed to proceed at reflux for 48-110 hrs, and then the desired macrocyclic tetraamide is isolated in good yield.

The method of the present invention can be used to prepare the macrocyclic intermediate important to the synthesis of oxidatively robust macrocyclic tetraamides shown in Structure 1. The synthesis of oxidatively robust macrocyclic tetraamides requires that all H atoms α to the N-donor atoms be replaced by more oxidatively robust groups such as alkyl, halo, aryl or heterocyclic substituents. ##STR7## wherein Y1, Y3 and Y4 each represent one, two or three carbon containing nodes for substitution, as explained in more detail herein, and wherein Y1 also represents zero carbon containing nodes. Structure 1 shows the key intermediate for the method of the present invention, an oxidatively robust macro linker (Arm-Linker-Arm). This molecule can be readily synthesized in one step without the use of protecting groups.

In an alternative embodiment, the method of the invention uses protection/deprotection sequences to generate a protected form of the macro linker intermediate. Upon deprotection, the intermediate is coupled via the double coupling reaction described above to generate the tetraamido macrocycle. Similarly, protection/deprotection sequences can be applied to substituents present on the bridging unit to widen the range of bridging substituents that can be utilized in the macrocyclization reaction.

Both embodiments of the method of the invention rely heavily on the amine and carboxylic acid based starting materials hereinafter listed in Table 1. Table 1 lists several forms of the starting materials in what is designated the parent, protected/activated and hidden forms of the amine and carboxylic acid functionalities in a general sense.

As used herein "parent groups" (shown in italics in Table 1) define a preferred synthetic functionality. "Protected/activated groups" refers to those groups that contain an easily recognizable portion of the parent group. "Hidden groups" as used herein refers to those groups that need not contain an easily recognizable portion of the parent group but which are capable of ready conversion to the parent group or to a protected/activated form of the parent group. More detailed examples may readily be found in Greene and Greene, "Protective Groups in Organic Synthesis", Johr. Wiley and Sons, New York (1981). An extensive list of protecting/activating groups particularly suitable for peptide synthesis may be found in G. A Fletcher and J. H. Jones, "A List of Amino-Acid Derivatives Which are Useful in Peptide Synthesis", int. J. Peptide Protein Res. 4, (1972), p.347-371. Common protection and deprotection steps for amines and carboxylic acids are shown schematically in Sequences 4(a)-(d) below. ##STR8##

The categories shown in Table 1 are utilized in Table 2 in conjunction with chelation ring size constraints (5- and 6-membered chelate rings are preferred) in order to identify useful starting materials for the synthesis of chelating macrocyclic tetraamide compounds having the desired five- or six- membered ring-containing structure.

Structure 2 is used herein to define the shorthand notation shown in Table 2 and Table 3 that specifies the chelate ring sizes (including the metal ion) that are formed when a given macrocyclic ligand is coordinated to a transition metal center. ##STR10##

Structure 2 illustrates a (5,5,5,5) macrocyclic ligand shown in metal coordinated form with chelate ring sizes (including the metal ion) indicated. Using a counterclockwise rotation, the specific macrocycle employed is 5aa-5ca-5cc-5ac- (or any cyclic permutation thereof). Amine functionalities are indicated by (a) and carboxylate functionalities are indicated by (c). Dashes (-) indicate amide bonds. Every dash must connect a trailing "a" to a leading "c" or vice versa, the final dash wraps around to the beginning.

The parent (=) forms of the functional groups for each starting material are shown pictorially in Table 2 below, while possible combinations of protected/activated (p/a) or hidden (h) forms for each starting material are shown in tabular form. Variable positions are marked with a bullet (). The underlined side captions are in a shorthand notation that refers to chelation ring sizes formed when the particular starting material is incorporated into a macrocycle and coordinated to a metal center.

The complete range of macrocyclic tetraamide compounds able to be synthesized from the starting materials identified in Table 2 is shown in general terms in Table 3. Each of the 43 unique combinations has been listed pictorially and labelled with the shorthand notation of structure 2 defined above.

The individual Bridge, Arm and Linker starting materials can either be obtained commercially or synthesized by standard techniques. Examples of syntheses for a few noncommercially available starting materials are provided herein and in the Experimental Section. A powerful alternative route for the preparation of substituted and unsubstituted malonates has been reported by A. P. Krapcho, E. G. E. Jahngen, Jr. and D. S. Kashdan. "α-carbalkoxylations of carboxylic acids. A general synthetic route to monoesters of malonic acids", Tet. Lett. 32, p.2721-2723 (1974). The oxidatively robust macrocyclic tetraamides shown in Table 3 may be synthesized without having to resort to the use of high energy intermediates or species that contain high energy N--N bonds, such as hydrazines, azides and azo constituents.

Schematics 1 to 3 below pictorially demonstrate substitution at the variable positions shown by a  in Table 3. The remainder of this section discusses how to choose R substituents in general terms, and lists some representative examples of substituted Bridge, Arm and Linker starting materials in tabular form. Finally a mathematical method for the enumeration of all of the different possible macrocyclic tetraamides that can be constructed within a given class from a given list of Bridge, Arm and Linker starting materials is presented (e.g. the lists of representative examples of substituted Bridge, Arm and Linker starting materials shown in Tables 4-6).

Single Node Substitution

Starting materials containing only one variable position are substituted by a carbon atom bearing two R groups, a --C(Ra) (Rb)-- unit, (in this context the dashes (-) refer to single bonds as opposed to amide bonds). See Schematic 1. ##STR25## Schematic 1: Replacement of a single variable position is always by a --C(Ra) (Rb)-- unit.

For substitution at any single variable position the R groups on the --C(Ra) (Rb)-- unit may be the same or different and are selected from the group consisting of hydrocarbons and heteroatom (e.g., halogen, N, O, Si, P, S) substituted hydrocarbons. Specific choices for the R groups are from the following types/subtypes either singly or in combination (e.g. for R=arylsilylester, only aryl, esters and siloxanes are listed); H, ketones, aldehydes, carboxylic acids, hidden or protected/activated carboxylic acids (see Table 1), esters, ethers, amines, hidden or protected/activated amines (see Table 1), imines, amides, nitro, sulphonyls, sulfates, phosphoryls, phosphates, silyl, siloxanes, alkyl, alkenyl, alkynyl, halo, aryl, and compounds chosen from biological systems e.g. natural or unnatural amino acid sidechains, heterocyclic rings, lactams, lactones, alkaloids, terpenes (steroids, isoprenoids), lipid or phospholipid chains.

For single node substitution, fusion of the Ra and Rb groups at a position that is not the site of substitution, but α to the site of substitution yields a species doubly bonded to the node such as an oxo (═O), imine (═NRa), or a substituted vinyl group (═CRa Rb). Formation of imines or substituted vinyl groups constitutes a form of nodal migration. If the original Ra and Rb groups are fused at a site that is not the site of substitution and is not α to the site of substitution then a cyclic ring structure is formed. If such cyclic groups are formed, additional R substituents on the cyclic groups are chosen in the same manner as for normal single node or multi node substitution (including the possibility of further R group fusions at one or more nodes to yield additional oxo, imine, substituted vinyl groups, or spiro, benzo, substituted benzo, heterocyclic, substituted heterocyclic, cycloalkyl, substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl ring structures). Preferred spiro/cyclic ring sizes are four, five or six membered rings. ##STR26## Schematic 2: Replacement at two variable positions can be by two --C(Ra) (Rb)-- units or the two variable positions can be combined to make up part of an aryl or heterocyclic ring structure.

For multiple node substitution individual --C(Ra) (Rb)-- positions are substituted identically as for single node substitution (see above). In addition to the types of substitution found for single nodes, it is also possible to combine or connect multiple nodes together via fusion of the R groups located on different nodes at sites that either are (combination), or are not (connection), the sites of attachment. Combination of sites that are adjacent leads to ethylenic units (--C(Ra)═C(Rb)--) a form of R group elimination. Connection of nodes via R group fusion at sites that are not the points of attachment or combination of sites that are not adjacent leads to the formation of cyclic structures, such as spiro, benzo, substituted benzo, heterocyclic, substituted heterocyclic, cycloalkyl, substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl ring structures. Four, five and six membered rings are preferred.

If cyclic groups are formed, or if there are residual R groups remaining from combination at adjacent sites, the residual R groups and the substituents on the cyclic groups are chosen in the same manner as for normal single node or multi node substitution (including the possibility of further R group fusions to yield additional spiro, benzo, substituted benzo, heterocyclic, substituted heterocyclic, cycloalkyl, substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl ring structures).

An important point is that the definitions for both single node and multi node substitution can function recursively, e.g. substituted o-phenylene diamine=>substituted heterocyclic o-phenylene diamine=>substituted spiro-cycloalkyl heterocyclic o-phenylene diamine etc. ##STR27## Schematic 3: Replacement at three variable positions can either be by three --C(Ra) (Rb)-- units or two of the variable positions can be combined to make up part of an aryl or heterocyclic ring structure with the third position being replaced by a --C(Ra) (Rb)-- unit or the three variable positions can all be combined to form part of a fused diaryl, fused aryl heterocyclic, or fused diheterocyclic ring structure.

Some representative examples of commercially available and/or synthetically versatile Linker, Arm and Bridge starting materials are shown in Tables 4, 5 and 6, respectively. A macrocyclic tetraamido compound having the desired chelate ring configuration shown in Table 3, i.e., 5555, 5556, 5656, 5566, 5666 or 6666, can be constructed by reference to the general choice and combination of starting materials for various chelate configurations shown in Table 2, i.e., parent, protected/activated or hidden, followed by the choice of the specific starting materials from Tables 4, 5 and 6. Use of those starting materials in the method of the present invention will provide a macrocyclic tetraamido compound having a chelate ring configuration and substituent array suited to a particular end use.

Table 4 identifies some representative dicarboxylic acid malonate or oxalate derivatives, i.e. Linkers, of interest for the preparation of macrocyclic tetraamides, either in parent, hidden, or protected/activated forms.

Table 6 identifies some representative diamines, i.e. Bridges, of interest for the preparation of macrocyclic tetraamides, either in parent, hidden, or protected/activated forms. Amine and protected/activated or hidden amine functionalities are used interchangeably.

The list of n, n+2-Diamines is significantly shorter than for the other derivatives, in large part because the syntheses of the required n,n+2 diamines are more complex than for the n, n+1 diamines.

In order to effectively discuss substitutions at all of the variable positions simultaneously, as in a substituted macrocyclic tetraamide compound, a sum over all of the possible combinations of the basic structural units may be constructed; bridges, B, arms, A, and linkers, L. This type of sum approach (a form of combinatorial analysis) provides a powerful method for the enumeration of all of the possible substituted macrocycles that can be constructed from any given list of substituted starting materials, for instance the lists previously cited. The combinatorial method proceeds as follows;

For any given class of macrocyclic tetraamides the connectivities of the bridge, arm and linker units is fixed e.g. Bridge-Arm-Linker-Arm-. Substitution at the variable positions then proceeds according to the rules stated previously. Some examples of the approach are shown in FIG. 1 and Eqn. 1. FIG. 1 shows some examples of substitution at the variable positions within the Bridge-Arm-Linker-Arm- group of macrocyclic tetraamides. The sum over all possible different combinations of bridges, B, arms, A, and linkers, L, is shown in Eqn. (1); ##EQU1## Asymmetric and/or chiral starting materials are accommodated in the numerical indices (i,j,k,l) of Eqn. (1) through enumeration of the different internal arrangements of R groups within the bridges, arms and linkers. Some specific examples of bridge, arm and linker starting materials are shown in Table 7. In each case the amide bonds have been retrosynthetically decomposed to form an amine equivalent (amine, nitro, azide, isocyanate, etc. see Table 1) and a carboxylic acid equivalent (acid, ester, acyl chloride, nitrile etc. see Table 1).

The bridges and linkers of Table 7 conserve local two fold symmetry while all of the arms shown lead to 5 membered chelate rings, therefore although direct application of Eqn. (1) will yield 135 terms (5 bridges×3 arms×3 arms×3 linkers) some of the terms will be duplicates of molecules that have already been enumerated. Specifically the two fold symmetry allows for exchange of the arm positions; i.e. Bi Aj Lk Al =Bi Al Lk Aj. This allows Eqn. (2), a more concise form of Eqn. (1) that includes the effects of two fold symmetry, to be utilized to enumerate just the unique combinations. ##EQU2##

The 90 unique combinations arising from application of Eqn. (2) to the B, A, and L units of Table 7, are shown in Table 8. Synthetic details for the preparation of many of the examples listed in Table 8 are given in the experimental section. Table 8 provides an enumeration of the group of 90 macrocyclic tetraamido molecules able to be constructed from the starting materials of Table 7 with application of Eqn. (2).

Entries shown with bold face and a solid box in Table 8 are shown specifically in the structures below. ##STR33## These structures provide a few specific examples of macrocyclic tetraamides that have been constructed from the starting materials of Table 7 via the method of the present invention. The captions utilize a running numerical index to indicate the position of the specific starting material in a given list of possible starting materials, e.g. B2 refers to the second Bridge in some specified list of Bridges. See, Eqn 1.

Since numerous variations of substituted α and β amino acids, activated malonate derivatives and substituted diamines are available commercially or can be easily made by known techniques, macrocyclic compounds having a much wider variety of substituents can be synthesized easily by the method of the present invention than heretofore possible by the prior art azide method.

Treatment of the macrocyclic tetraamides with strong noncoordinating bases and exposure to transition metal salts leads to the formation of chelate compounds possessing four amido-N to metal bonds. When placed in an oxidizing media these chelate compounds can function as robust oxidation catalysts. As used herein, robust oxidation catalyst means that when the catalyst is added to a solvent in the presence of an oxidant, such as a peroxide, the half-life of the activated form of the metal complex is 30 seconds or more. The half-life is the time in which half of the metal complex decomposes or degrades. A preferred design for producing robust ligands is a macrocyclic tetraamido ligand having no hydrogens α to the N-amido donor groups.

A preferred tetraamido macrocycle prepared by the method of the invention has the following structure: ##STR34## wherein Y1 to Y4 each represent one, two or three carbon containing nodes for substitution and Y, can also represent zero carbon containing nodes. Each node is a C(R) or C(R)2 wherein each R substituent is the same or different, pairwise and cumulatively, from the remaining R substituents and is selected from the group consisting of alkyl, or alkenyl, aryl, hydrogen, halogen, CF3 and combinations thereof or any of the substituents referenced herein, or together with a paired R substituent bound to the same carbon atom form a cyclopentyl or cyclohexyl ring. Pairs, particulary pair, R1, R2, of Y1, may be nonlinked, or linked to form a spiro/cyclo form of substituent.

Y2 is preferably selected from the group consisting of ##STR35## wherein R3 and R4 are the same or different, pairwise and cumulatively, and are alkyl, aryl, hydrogen, halogen, CF3, or any of the substituents referenced herein; and

Macrocycles with spiro-cyclohexyl substituents have been prepared by the present method and found to render the macrocycle very hydrophobic. Long chain substituents, such as a dodecyl chain, or phospholipid chain will render the macrocycle soluble in membranes.

The spiro-cyclohexyl derivative is sterically hindered and has slower reaction rates than the other preferred substituents, so the normal synthesis of the amide intermediate of the first step of the method of the invention is altered.

Synthesis of the bis spiro-cyclohexyl macro linker intermediate was accomplished by adding acylating agent dropwise in multiple aliquots, preferably three, separated in time. Twelve hour intervals followed by extended reaction periods produced the best results. Without the extended reaction periods, the yield was lower. The reaction sequence is shown in thr sequences below. Cyclohexane can be used to separate the oxazalone form of the macro linker away from the other reaction products, or water can be added to hydrolyze the oxazalone in situ. Hydrolysis of the intermediate oxazalones provides an increased yield of the desired bis cyclohexyl product. ##STR36##

Hydrolysis of a hydrophobic oxazalone The cyclohexyl-containing macro linker is then ready for ring closure in the same manner as other amide intermediates of the primary method of the invention. However, due to the enhanced stability of the spiro-cyclohexyl containing macrocyclic intermediates, separation of the macrocycle from reaction by-products differs from other preferred ring closing constituents. Typically, the crude macrocyclic product is extracted into an organic solvent, such as CH2 Cl2. The CH2 Cl2 solution is washed with acids and bases to remove the impurities and side products that contain acidic and basic functionalities and to hydrolyze any oxazalone containing intermediates. The cyclohexyl tetraamido macrocycle is not well purified by the usual acid/base washes yielding instead an approximately 1:1 mixture of the bis cyclohexyl oxazalone and bis-cyclohexyl tetraamido macrocycle. Pentane extraction of the mixture yields a clean separation. The macrocycle is insoluble and isolated as a powder, while the pentane soluble fraction can be evaporated to yield large crystals of the bis cyclohexyl oxazalone.

Table 9 shows the dependence of the yield on the amount of diethyl malonyl dichloride used in the synthesis of some macro linker intermediates (Arm-Bridge-Arm).

Addition of an excess of the substituted malonyl dichloride improves the yield of macro linker with an optimum ratio of about 2 moles of amino acid to 1.35 to 1.5 moles of the substituted malonyl dichloride. The product mixture includes the macro linker and a mono oxazalone form of the macro linker which can be readily hydrolysed to yield additional product. The yield of the method is improved significantly if water is excluded from the reaction solution during ring closure reactions. FIG. 2 illustrates an original design for a long-necked RB flask utilized in the ring closure step of the primary method of the invention. This type of air cooled condenser is preferred for performing lengthy macrocyclization reactions in refluxing high boiling (b.p.>100° C.) solvents. A clamp placed halfway up the neck not only serves to secure the flask and its contents but also acts as an additional heat sink to prevent hot solvent vapor from rising too high up the neck. In a normal reflux apparatus, the joints are located much closer to the RB flask and the hot solvent vapors can readily melt/dissolve the grease in the fittings or leak past TEFLON joint sleeves.

Pyridine diamines can also be utilized. The prior art azide synthetic route, which includes a reduction step that also reduces the pyridine ring, does not yield a macrocyclic compound having a pyridine bridge. Amino pendant variations would also be tedious to synthesize by the prior art method. The amino pendant variations are of considerable interest because they permit the macrocyclic compound or metallocomplex to be tethered to a support, such as a polymer or sand, or to other molecules or substrates having functional groups which will covalently bond with the amine. Groups which covalently bond with amines are well known in the art and include in complexed form, for example, alkyl amines, amides, sulphonamides, imines, and other hidden or protected/activated forms, see Table 1.

The synthesis of the aryl amino pendant macrocycle proceeds generally as in Sequences 6 and 7. ##STR37## Synthesis of 1,2-Diamino-4-Acetamidobenzene (dihydrobromide)

Note the strategic and selective introduction of a protected amino group (an acetamide) onto the aryl diamine group (Bridge). The protected form of the bridge, an acetamide diamine, is then suitable for ring closure via the standard diamine+intermediate linker synthetic routes described herein. An extended ring closure time is required to achieve macrocyclization and is attributed to unfavorable hydrogen bond formation between the attached oxazalone and the acetamido group, which would be expected to slow down the desired macrpcyclizaticn reaction.

Once the protected amino pendant macrocycle has been synthesized as in sequence 5, it can be metallated with cobalt. Removal of the acetyl protecting group then yields a macrocyclic cobalt complex that is ready to be attached to a support. Best results to date have been obtained by reacylating the pendant amino group with acryloyl chloride to yield an amide linked vinyl pendant macrocycle. ##STR38## Synthesis of an Amino Pendant Macrocyclic Cobalt Complex

This may then be copolymerized with a twenty fold excess of various acryloyl monomers to yield an acrylic polymer that contains a macrocyclic cobalt complex as a sidechain approximately every 20 residues, shown schematically in FIG. 3.

By anchoring the macrocyclic metal complex to a polymer or some other support, the metal may be reclaimed and recycled according to the system shown schematically in FIG. 4. Environmentally toxic metals, for example CrVI can be replaced by more environmentally benign oxidation reagents, such as CoIV or CoIII LI species, where LI refers to a ligand centered oxidation.

Referring to FIG. 4, following the desired oxidation process, the anchored oxidant can be recycled via collection and reoxidation with a primary oxidant, such as hypochlorite, bromine or by electrolysis. Use of anchored macrocyclic metal species is expected to provide a viable method to significantly reduce the levels of discharge of toxic spent metallic species into the environment. The polymer bound oxidant system of FIG. 4 serves as an example of a recyclable "Green" oxidation reagent.

EXPERIMENTAL SECTION

Syntheses of Oxidatively Robust Tetraamido Ligands.

Materials. All solvents and reagents were reagent grade (Aldrich, Aldrich Sure-Seal, Fisher) and were used as received. Microanalyses were performed by Midwest Microlabs, Indianapolis, IN.

Electrochemical Measurements. Cyclic voltammetry was performed under N2 in a three compartment cell using a glassy carbon disk working electrode (A˜0.0078 cm2 or 0.071 cm2), a Pt wire counter electrode, and a sodium chloride saturated calomel electrode (SSCE) as reference. CH2 Cl2 (Aldrich Sureseal) or CH3 CN (dried over CaH2) were employed as solvents with a supporting electrolyte of [Bu4 N][ClO4 ] (0.1 M, Fluka, vacuum dried 24 h ° C.) or [Bu4 N][PF6 ] (0.1 M, Fluka puriss). A Princeton Applied Research Model 273 Potentiostat/Galvanostat controlled with a Compudyne 486DX computer was used and current/voltage curves were recorded on a Graphtec Model WX1200 X-Y recorder, or using a Princeton Applied Research Model 173/179 potentiostat/digital coulometer equipped with positive feedback IR compensation, a Model 175 universal programmer, and a Houston Instruments Model 2000 X-Y recorder. For some experiments, ferrocene (Fc) was added as an internal potential standard at the conclusion. Formal potentials were calculated as the average of anodic and cathodic peak potentials and are reported vs NHE. Peak-to-peak separation of the Fc+ /Fc couple was similar to that of the iron compound couples in all cases. Plots of peak current vs. the square root of scan speed over the range 20-500 mV s-1 were found to be linear for all couples.

Mass Spectrometry. Electrospray ionization mass spectra were acquired on a Finnigan-MAT SSQ700 (San Jose, Calif.) mass spectrometer fitted with an Analytical of Branford electrospray interface. Electrospray voltages of 2400-3400 V were utilized. Samples were dissolved in either acetonitrile or dichloromethane at concentrations of approximately 10 pmol/μl and were introduced into the ESI interface prior to data acquisition by direct infusion at a flow rate of 1 μl/min and were introduced prior to data acquisition. Positive ion electron impact ionization (70 ev) MS experiments were performed on a Finnigan-MAT 4615 quadrupole mass spectrometer in conjunction with an INCOS data system. The ion source temperature was 150° C. and the manifold chamber temperature was 100° C. Sample introduction was by means of a gas chromatograph or a direct insertion probe. Positive ion fast atom bombardment mass spectra were acquired on a Finnigan-MAT 212 magnetic sector instrument in combination with an INCOS data system. The accelerating voltage was 3 kV and the ion source temperature was approximately 70° C. An Ion Tech saddle field fast atom gun was employed with xenon at 8 keV. Thioglycerol was utilized as the FAB matrix. Positive ion electron impact ionization (70 eV) MS/MS experiments were performed on a Finnigan-MAT TSQ/700 tandem quadrupole mass spectrometer. Sample introduction was by means of a direct insertion probe. The ion source was maintained at 150° C. and the manifold chamber was held at 70° C. Collision-induced dissociation (CID) was achieved by introducing argon into the center rf-only collision octapole until the pressure in the manifold reached 0.9-2.5×10-6 Torr. The nominal ion kinetic energy for CID product ions was <35 eV (laboratory reference). High resolution data were obtained on a JEOL JMS AX-505H double focusing mass spectrometer in the EB configuration using a resolution of 7500. Sample introduction was by means of a gas chromatograph or direct insertion probe. During mass spectral acquisition, perfluorokerosene was introduced into the ion source by means of a heated inlet. Exact mass assignments were obtained by computer-assisted interpolation from the masses of perfluorokerosene. GC/MS conditions: column, 20 m×0.25 mm DB-1701 (J & W Scientific); carrier gas, helium with a linear velocity of 40 cm/sec; injector, 125° C.; column temperature, 35° C. for 3 min, followed by an increase at 10° C./min to 100° C.; injection, split mode, appx. 50:1 ratio.

Spectroscopic Methods. 300 MHz 1 H NMR spectra and 75 MHz 13 C NMR spectra were obtained on an IBM AF300 instrument using an Oxford Superconducting magnet system, data acquisition was controlled by Bruker software. Infrared spectra were obtained on a Mattson Galaxy Series 5000 FTIR spectrometer controlled by a Macintosh II computer. UV/vis spectra were obtained on a Hewlett Packard 8452A spectrophotometer driven by a Zenith Z-425/SX computer. Conventional X-Band EPR spectra were recorded on a Bruker ER300 spectrometer equipped with an Oxford ESR-900 helium flow cryostat. Mossbauer spectra were obtained on constant acceleration instruments and isomeric shifts are reported relative to an iron metal standard at 298 K. In order to avoid orientation of polycrystalline samples by the applied magnetic field, the samples were suspended in frozen nujol.

A solution of 2,4-Dibromo-2,4-dimethylpentanone prepared as above or purchased from Lancaster Synthesis (89.8 g, 0.33 mol) in EtOH (1.2 L, 95%) was added to a solution of NaN3 (Caution!, 47.2 g, 0.726 mol, 2.2 equiv) in water (0.6 L). The solution was heated under reflux (16 h) to give a pale orange solution. The EtOH was removed under reduced pressure until the solution became cloudy. The cloudy aqueous solution was extracted, still warm, with pentane (500 mL) three times, and the combined extracts were dried over Na2 SO4 and concentrated to 300 mL under reduced pressure. Glacial acetic acid (100 mL) was then added, and the remaining pentane was removed under reduced pressure. This workup was required to remove any excess NaN, since the product is exposed to Pd/C in the next step, and care should be taken to avoid the formation of heavy metal azides (due to the risk of explosion). The solvent was removed from a small sample under reduced pressure to give a neat oil (<20 mg) for spectroscopic characterization: 1 H NMR (CDCl3): 1.54 (s). IR (neat) ν [cm-1 ]: 2115 (RN3), 1720 (ketone CO). It should be noted, for safety, that the organic azides produced in this and related azide based syntheses are never isolated in concentrated forms or as solids in quantities greater than 20 mg.

2,4-Diamino-2,4-dimethylpentan-3-one:

Glacial acetic acid (50 mL) was added to the HOAc solution of the dialkyl azide formed in the previous step, and this solution was added to 10% Pd/C (2.7 g). The mixture was hydrogenated at 50 psi (1 week) in a Parr hydrogenator. Because the reaction evolves one N2 molecule for every H2 molecule absorbed, the bomb was evacuated and repressurized 10 times with H2 to 50 psi. (H2 from the high pressure reservoir is not efficiently consumed.) The charcoal was removed by filtration, and HOAC was removed under reduced pressure. After HBr was added (48%, 76 mL), the mixture was dissolved in EtOH. The volatiles were removed under reduced pressure to yield a tan solid, which was washed with a mixture (200 mL) of THF (50%), EtOH (45%), and conc. HBr (5%) or with a mixture of THF (95%) and conc. HBr (5%). The resulting white powdery product was the dihydrobromide salt of 2,4-Diamino-2,4-dimethylpentan-3-one (56.2 g, 48% from 2,4-Dibromo-2,4-dimethylpentanone). Additional product may be collected from washings that have been pooled from several different preparations. The product must be stored as the dihydrobromide or dihydrochloride salt to protect the amines from oxidative degradation. Characterization: 1 H NMR (CDCl3 /DMSO-d6) of 2,4-diamino-2,4-dimethyl-pentan-3-one. 2 HBr: 8.62 (6H, s, br, NH3), 1.77 (12 H, s, Me). IR (free base, nujol mull) ν [cm-1 ]: 3460-3160 (RNH2), 1690 (ketone CO). Anal. (Dried at 80° C.) Calcd for C7 H16 N2 O. (HBr)2 : C, 27.47; H, 5.93; N, 9.15; Br, 52.22. Found: C, 27.43; H, 5.91; N, 9.11; Br, 52.46.

A two-neck flask (2 L, RB+Claisen) fitted with a pressure equalizing addition funnel (250 mL) and septa, is placed under N2. α-aminoisobutyric acid (i.e. α-methyl alanine) (90.3 g, 0.9 mol) is added, anhydrous pyridine (1.4 L, sure seal) is cannulated into the flask and the reaction mix heated to 45-55° C. and stirred. Pyridine (100 mL, sure seal) and then diethyl malonyl dichloride (104.4 mL, 0.61 mol) are cannulated into the addition funnel. The contents of the addition funnel are added (dropwise, 3-4 h) to the reaction, the addition funnel is then removed, and the acylation allowed to proceed (55-65° C., 120-130 h) under N2. Once the acylation is complete the reaction is quenched by adding H2 O (100 mL) and stirring (60-70° C., 24-36 hrs). The solvent volume is reduced on the rotary evaporator to give an oil, then HCl (conc., ca. 110 mL) is added to a final pH of 2-3. The hot solution is set in the refrigerator (4° C., 15 h), and the resulting tan product collected by frit filtration, and washed thoroughly with acetonitrile (700 mL, 150 mL) by stirring in an erlenmeyer flask. The air-dried white product (87.9 g, 60% yield), is crushed in a mortar and pestle and stored in a dessicator. The large scale reaction amide intermediate product is more likely to need recrystallization before use in ring closure reactions.

EXAMPLE 4

Recrystallization of the TMDE substituted intermediate from above Crude TMDE intermediate from Example 3 (50.4 g, 0.153 mol) is dissolved in H2 O (500 mL, deionized) by adding Na2 CO3 (16.2 g, 0.153 mol) in three aliquots slowly and carefully to avoid excessive frothing, with good stirring and mild heating. The solution is brought to a boil, filtered and acidified with HCl (conc., 30 mL, 0.36 mol). The solution is allowed to cool (overnight, 4° C.) and the white precipitate filtered off and washed with acetonitrile (250 mL). The air dryed product (38.8-45.4 g, recryst. yield 77-90%) should be stored in a dessicator.

Crude hexamethyl (HM) intermediate was recrystallized in the same manner as the TMDE amide intermediate. Due to the slightly higher water solubility of the HM amide intermediate a little less H2 O should be employed.

Examples of several synthetic routes for the preparation of macrocyclic tetraamido ligands follow.

Phosphorus Trichloride Coupling

Phosphorus trichloride coupling of the amide-containing intermediate (A--L--A) to aromatic 1,2-diamines yields macrocyclic tetraamides safely, cheaply and in high yield. Two distinct variations of the PCl3 coupling method are useful, the differences relate to the order of addition and choice of reagents utilized. These methods are applicable to the preparation of a wide variety of different macrocycles with different electronic substituents present on the bridge diamine, or steric substituents present on the amide intermediate, primarily because of the parallel incorporation of the macro linker type of amide intermediates into all of the syntheses.

EXAMPLE 9A. Macrocycle Synthesis via PCl3 Coupling

A long neck flask (250 mL) is charged with the amide intermediate of Examples 2-8, (10 mmol) a stir bar and then baked in the oven (80-100° C., 30-45 mins). The hot flask is placed under N2, aryl diamine (10 mmol) is added and anhydrous pyridine (50 mL, sure seal) cannulated in. The flask is heated (50-60° C.) and PCl3 (d=1.574 g/mL, 1.72 mL, 20 mmol) syringed in as quickly as possible without excessive refluxing. This is an exothermic reaction, so caution should be used. The temperature is then increased to reflux or just below reflux (100-115° C.) and the reaction allowed to proceed under N2 (48 h). After the acylation is complete, the contents of the flask are acidified with HCl (1 eq., ca. 60 mL) to a final pH≈2. The mixture is transferred to an erlenmeyer (water is used to rinse the flask) and stirred with CH2 Cl2 (300 mL, 2-3 h), then extracted with additional CH2 Cl2 (2×150 mL). The combined organic layers are washed with dilute HCl (0.1 M, 2×100 mL) followed by dilute aqueous Na2 CO3 (2×5 g/100 mL). The organic solvents are removed on the rotary evaporator to yield crude product (30%). The weight of crude product is usually equivalent to the initial weight of diamine.

B. Macrocycle Synthesis via PCl3 Coupling

A long neck flask (250 mL) is charged with MgSO4 (5 g), a stir bar, aryl diamine (10 mmol) and pyridine (50 mL, dryed over 4 Å mol sieves) then placed under N2. PCl3 (d=1.754 g/mL, 1.72 mL, 20 mmol) is added via syringe and the mixture brought to reflux for 30 mins, an orange/yellow precipitate forms. The mixture is cooled somewhat, an amide intermediate (10 mmol) is added, then the mixture is refluxed under N2 (115° C., 48 h). After the acylation is complete, the contents of the flask are acidified with HCl (1 eq., ca. 60 mL) to a final pH≈2. The mixture is transferred to an erlenmeyer and stirred with CH2 Cl2 (300 mL, 2-3 h), then extracted with additional CH2 Cl2 (2×150 mL). The combined organic layers are washed with dilute HCl (0.1 M, 2×100 mL) followed by dilute Na2 CO3 (2×5 g/100 mL). The organic solvents are removed on the rotary evaporator to yield crude product (30%). The weight of crude product is usually equivalent to the initial weight of diamine.

Note: For larger scale macrocyclization reactions, the ring closure times are increased to 4-5 days at reflux, and most of the pyridine present at the end of the reaction is removed via rotary evaporation prior to acidification.

Oxazalone coupling of the amide intermediate to aromatic diamines also yields macrocyclic tetraamides safely, cheaply and in high yield, but with less sensitivity to additional functional groups. All of the macrocycles able to be formed via the PCl3 coupling route with the exception of the CyHex substituted macrocycles (too sterically hindered) can also be manufactured via the oxazalone coupling route. In addition the lesser sensitivity to additional functional groups has opened up the preparation of macrocyclic ligands with additional functional groups designed to confer new properties on the resulting metal complexes. Specific examples include the incorporation of reactive groups (such as amine or vinyl groups) attached in a pendant fashion to the aryl ring of the macrocycle allowing for covalent attachment of the preformed macrocycles to some (polymeric) substrate.

EXAMPLE 20Macrocycle Synthesis via Oxazalone Method

A long neck flask (250 mL) is charged with amide intermediate (3.3 g, 10 mmol), a stir bar and then baked in the oven (80-100° C., 30-45 mins). The hot flask is fitted with a septum and placed under N2. Anhydrous pyridine (50 mL, sure seal,) is cannulated in and heating commenced while trimethyl acetyl chloride (i.e. pivaloyl chloride) (22-24 mmol) is added via syringe. The temperature is increased to reflux or just below reflux (100-115° C.) and the reaction allowed to proceed under N2 (22-26 h) being careful to avoid cross contamination from other reactions on the N2 line. The reaction goes from a clear pale yellow to a yellow-brown color. After oxazalone formation is complete.sup.§, the aryl diamine (8-10 mmol) is added either as a neat solid or via large bore cannula as a slurry in anhydrous pyridine, or dissolved and degassed under N2 in anhydrous (sure seal) pyridine, if head space and solubility constraints can be satisfied. The ring closure reaction is refluxed for a further 48-72 hours (longer times for larger scales) under N2 without cross contamination from other reactions. The mixture will usually turn brownish black. Once the acylation is complete, the reaction is quenched by adding H2 O (30 mL) and stirring at reflux 100° C., 22-26 hrs). The mixture is cooled and transferred to an RB flask (500 mL) using a minimum of H2 O to rinse the long neck flask. The solvent is removed via rotary evaporation to yield the crude product mixture as an oily tan to brownish black solid. It should be noted that, functional groups permitting, the crude product mixture can be taken up in CH2 Cl2 and washed with dilute aqueous HCl and dilute aqueous Na2 CO3. Removal of the organic solvent at reduced pressure then yields the normal macrocyclic product familiar from the PCl3 coupling reactions and suitable for direct recrystallization as detailed previously to yield pure macrocyclic product.

EXAMPLE 22Synthesis of a peralkylated macrocycle (MAC*), or TMDE-DMP from the TMDE intermediate+2,4-Diamino-2,4-dimethyl-Pentan-3-one (DMP) via the Oxazalone Route

The PCl3 route to H4 [MAC*] (TMDE-DMP) fails to produce appreciable amounts of macrocycle due to what is speculated to be unfavorable complex formation between the diamine ketone functionality and the phosphorus reagent. Unlike the PCl3 route, which is heterogeneous, the oxazalone route to H4 [MAC*] is a homogeneous solution method which simplifies the application of diagnostic techniques such as 1 H NMR to diagnose causes of synthetic failure. Reaction of TMDE bis oxazalone with DMP diamine in dry pyridine fails to form any amides (by NMR analysis). Since the oxazalone route is insensitive to ketone functionalities, the failure to form amides was attributed to acid salt formation of the alkyl amine functionality, the alkyl diamine is 3-4 pKa units more basic than pyridine while aryl diamines have pKa 's close to that of pyridine. Therefore, a more basic high boiling solvent (triethylamine, tripropylamine, diethylaniline) may be used to increase the amount of amide formation. For amine containing solvents, the presence of water and impurity amines is problematic considering the low solubility of the reactants. Addition of a lewis acid drying agent was found to be beneficial. An appreciable yield of H4 [MAC*] was obtained (2-3% macrocyclization yield, unoptimized) from the reaction (1 step) of TMDE bis oxazalone with DMP alkyl diamine in refluxing dripropylamine+CaO. Isolation of the product was by fractional recrystallization from toluene in combination with 1 H NMR analysis.

The highest possible yield of H4 [MAC*] from alkyl diamine via the prior art method of Uffelman (4 steps from the alkyl diamine) is 8-10%. Clearly H4 [MAC*] can be obtained in appreciable yield via the oxazalone route.

[Ph4 P]5 [the tetraphenylphosphonium salt of iron(IV) cyano TMDE-DCB monoanion] can be formed in the presence or absence of base. In the absence of base, the blue color fades to yellow-orange as the solvent is removed in the workup procedures. Therefore, product isolation to obtain the blue solid is best carried out in the presence of added base at a pH range of 9-10. The following reaction yields 5 with each of CH3 CN, CD3 CN, CH3 CH2 CN and (CH3)2 CHCN as the solvent substrates. Base was not added to the catalytic reactions described. It was demonstrated that the blue compound is an effective catalyst precursor by adding isolated [Ph4 P]5 to an acetonitrile solution of TBHP (tertiary butyl hydroperoxide), both the solvent and oxidant were consumed indicating that although [Ph4 P]5 is formed as an end product of the catalytic oxidation process it is not a deactivated form of the catalyst.

C29 H48 Cl2 FeN5 O6, M=689.47, Triclinic, Space group P-1, a=9.899(2); b=11.771(2); c=14.991(4)Å, α=95.33(2); β=100.09(2); γ=92.31(2), V=1709.6(6)Å3, Dobs =1.33 g cm-3, Dcalcd (Z=2)=1.339 g cm-3, T=293 K, λ=0.71069 Å, μ=0.64 mm-1, trans coeff. 0.87-1.00. Diffraction data were collected at room temperature on an Enraff-Nonius CAD-4 diffractometer using graphite monochromated Mo-Kα radiation. Three reflections were monitored throughout data collection, only random fluctuations in intensity being observed. The structure was solved by direct methods. Hydrogen atoms bonded to the carbon were included in calculated positions with C--H bond distance of 0.96 Å and were refined using a riding model with a thermal parameter 20% greater than the parent carbon. Hydrogen atoms of the water molecule were located from electron density difference maps and their coordinates allowed to refine with the thermal parameter fixed at 20% greater than that of the oxygen. Refinement was by full-matrix least squares on F2 with scattering factors taken from the International Tables. All non-hydrogen atoms were refined with anisotropic thermal parameters. The final difference maps were featureless. Refinement converged to R=0.053, wR2=0.112 with weights 1.0/[σ2 (Fo2)+{0.0652(Fo2 +2 Fc2)/3}2 ] for 2262 observe reflections.

EXAMPLE 30X-ray Crystal Structure Data and Refinement for [Et4 N]4.

Single crystals of [Et4 N]4. at 20±1° C. are monoclinic, space group P21 /c-C52h (No. 14) with a=9.958(2) Å, b=14.956(3) Å, c=22.688(5) Å, α=90.00°, β=93.83(2)°, γ=90.00°, V=3372(1) Å3, and Z=4 (dcalcd =1.357 g cm-3 ; μa (CuKα)=6.17 mm-1). A total of 4626 independent absorption-corrected reflections having 2θ (CuKα) <115.0° were collected using θ-2θ scans and Ni-filtered CuKαradiation. The structure was solved using "Direct Methods" techniques with the Nicolet SHELXTL software package as modified at Crystalytics Company. The resulting structural parameters have been confined to a convergence of R1 (unweighted, based on F)=0.037 for 2680 independent reflections having 2θ (CuKα)<115.0° and I>3σ(I). The ten methyl groups were refined as rigid rotors with sp3 -hybridized geometry and a C--H bond length of 0.96 Å. The initial orientation of each methyl group was determined from difference Fourier positions for the hydrogen atoms. The final orientation of each methyl group was determined by three rotational parameters. The refined positions for the rigid rotor methyl groups gave C--C--H angles which ranged from 103°-118°. The remaining hydrogen atoms were included in the structure factor calculations as idealized atoms (assuming sp2 - or sp3 -hybridization of the carbon atoms and a C--H bond length of 0.96 Å) riding on their respective carbon atoms. The isotropic thermal parameter of each hydrogen atom was fixed at 1.2 times the equivalent isotropic thermal parameter of the carbon to which it is covalently bonded.

Richard J. Bushby and Michael D. Pollard, The Introduction of Alkylidene Substituents into the 4 Position of the 3,3,5,5, Tetramethyl pyrazoline Nucleus by the Thioketone plus Diazoalkane Reaction: Synthesis of Tetrasubstituted Episulphides and Alkenes.

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Richard J. Bushby and Michael D. Pollard, The Introduction of Alkylidene Substituents into the 4-Position of the 3,3,5,5,-Tetramethyl-.increment.-pyrazoline Nucleus by the Thioketone plus Diazoalkane Reaction: Synthesis of Tetrasubstituted Episulphides and Alkenes.